Azaspirodecanone compounds

ABSTRACT

The invention provides novel compounds having the general formula (I) 
                         
wherein R 1  and R 2  are as described herein, compositions including the compounds, their pharmaceutically acceptable salts and esters and methods of using the compounds.

PRIORITY TO RELATED APPLICATIONS

This application claims the benefit of European Patent Application No.11158703.6, filed Mar. 17, 2011, which is hereby incorporated byreference in its entirety.

FIELD OF THE INVENTION

The present invention relates to organic compounds useful for therapy orprophylaxis in a mammal, and in particular to inhibitors of hormonesensitive lipase (HSL) for the treatment of diabetes, metabolicsyndrome, dyslipidemia, atherosclerosis, obesity, cardiovasculardiseases, myocardial dysfunction, inflammation, nonalkoholic fatty liverdisease or nonalkoholic steatohepatitis.

BACKGROUND OF THE INVENTION

The main physiological role of white adipose tissue (WAT) is to supplyenergy when it is needed by other tissues. In mammals, white adiposetissue is the primary energy storage depot, accumulating fuel reservesin the form of triacylglycerol (TAG) during times of energy excess. Therelease of free fatty acids (FFA) from TAG is stimulated bycatecholamines and regulated by hormones such as insulin, glucagon andepinephrine. The most important enzyme in WAT believed responsible forhormone regulated hydrolysis of triglyceride is hormone sensitive lipase(HSL).

Dysregulation of adipocyte lipolysis, resulting in elevated circulatingnon-esterified fatty acids (NEFA) is associated with obesity andco-morbidities including the development of type 2 diabetes. Obese orinsulin resistant subjects have increased visceral adipose tissuedepots. These depots contain elevated levels of HSL protein and exhibitenhanced lipolytic activity as they are resistant to theinsulin-mediated suppression of lipolysis. This results in increasedplasma levels of free fatty acids (FFA), which further exacerbatesinsulin resistance due to the accumulation of triglycerides in tissuesother than WAT such as liver, pancreas and muscle. Thus, the elevatedplasma levels of FFA due to increased HSL activity contributes to andworsens insulin resistance in obese and type 2 diabetic individuals.Restoring the exaggerated plasma FFA and triglyceride levels throughinhibition of HSL would reduce the accumulation of triglycerides intissues other than WAT, such as liver, muscle and the pancreas resultingin decreased hepatic glucose output, increased muscle fatty acidoxidation and improving β-cell function.

Elevated FFAs are also associated with increased cardiovascular risk,including atherosclerosis and myocardial dysfunction. Furthermore highlipolytic activity and elevated FFAs lead to increased insulinresistance and hypertension in hypertensive rats. The FFA collect in theliver and lead to increased production of TAG, which are packaged intovery low density lipoproteins (VLDL) which are secreted. Therefore,reducing the activity of HSL would decrease the release of FFA to theblood, thus limiting the supply of FFA to the liver for TAG synthesis.Thus, HSL inhibitors could have beneficial effects as treatment ofnonalkoholic fatty liver disease (NAFLD) and nonalkoholicsteatohepatitis (NASH).

Objects of the present invention are the compounds of formula (I) andtheir aforementioned salts and esters and their use as therapeuticallyactive substances, a process for the manufacture of the said compounds,intermediates, pharmaceutical compositions, medicaments containing thesaid compounds, their pharmaceutically acceptable salts or esters, theuse of the said compounds, salts or esters for the treatment orprophylaxis of illnesses, especially in the treatment or prophylaxis ofdiabetes, metabolic syndrome, dyslipidemia, atherosclerosis, obesity,cardiovascular diseases, myocardial dysfunction, inflammation,nonalkoholic fatty liver disease or nonalkoholic steatohepatitis and theuse of the said compounds, salts or esters for the production ofmedicaments for the treatment or prophylaxis of diabetes, metabolicsyndrome, dyslipidemia, atherosclerosis, obesity, cardiovasculardiseases, myocardial dysfunction, inflammation, nonalkoholic fatty liverdisease or nonalkoholic steatohepatitis.

SUMMARY OF THE INVENTION

The present invention relates to a compound of formula (I)

whereinR¹ is selected from the group consisting of haloalkoxyalkyl,oxopyrrolydinylalkyl and oxopiperidinylalkyl; andR² is substituted phenyl or substituted pyridinyl, wherein substitutedphenyl and substituted pyridinyl are substituted with one to threesubstituents independently selected from the group consisting ofhaloalkyl, hydroxyhaloalkyl, alkoxy and haloalkoxy;or a pharmaceutically acceptable salt or ester thereof.

The present invention also relates to a pharmaceutical compositioncomprising a compound as described above and a therapeutically inertcarrier.

DETAILED DESCRIPTION OF THE INVENTION

The term “alkoxy” denotes a group of the formula —O—R′, wherein R′ is analkyl group. Examples of alkoxy group include methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. Particularalkoxy group include methoxy, ethoxy, n-propoxy and isopropoxy. Furtherparticular example is isopropoxy.

The term “alkyl” denotes a monovalent linear or branched saturatedhydrocarbon group of 1 to 12 carbon atoms, in particular of 1 to 7carbon atoms, more particular of 1 to 4 carbon atoms, for example,methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, andtert-butyl. Particular alkyl groups include methyl, ethyl, n-propyl andisopropyl. More particular alkyl group is methyl.

The term “haloalkoxy” denotes an alkoxy group wherein at least one ofthe hydrogen atoms of the alkoxy group has been replaced by same ordifferent halogen atoms. Examples of haloalkoxy include fluoromethoxy,difluoromethoxy, trifluoromethoxy, trifluoroethoxy,trifluoromethylethoxy, trifluorodimethylethoxy and pentafluoroethoxy.Particular haloalkoxy groups are trifluoromethoxy and trifluoroethoxy.More particular haloalkoxy group is 1,1,1-trifluoropropan-2-oxy.

The term “haloalkyl” denotes an alkyl group wherein at least one of thehydrogen atoms of the alkyl group has been replaced by same or differenthalogen atoms. Examples of haloalkyl include fluoromethyl,difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethylethyland pentafluoroethyl. Particular haloalkyl group is trifluoromethyl.

The term “halogen” and “halo” are used interchangeably herein and denotefluoro, chloro, bromo, or iodo. Particular halogens are chloro andfluoro. More particular halogen is fluoro.

The term “hydroxyhaloalkyl” denotes an alkyl wherein at least one of thehydrogen atoms of the alkyl has been replaced by a hydroxy group andwherein at least one of the hydrogen atoms of the alkyl has beenreplaced by a halogen. Examples of hydroxyhaloalkyl includehydroxytrifluoroethyl, hydroxytrifluoropropyl andhydroxyhexafluoropropyl. Particular hydroxyhaloalkyl is2,2,2-trifluoro-1-hydroxyethyl.

The term “oxo” denotes a divalent oxygen atom ═O.

The term “oxopiperidinyl” denotes a piperidinyl wherein two geminalhydrogens atoms of the piperidinyl have been replaced by an oxo group.Particular example is 2-oxopiperidinyl.

The term “oxopyrrolydinyl” denotes a pyrrolydinyl wherein two geminalhydrogens atoms of the pyrrolydinyl have been replaced by an oxo group.Particular example is 2-oxopyrrolydinyl.

The term “oxopiperidinylalkyl” denotes an alkyl wherein at least one ofthe hydrogen atoms of the alkyl has been replaced by anoxopiperidinylalkyl group. Particular example is2-oxopiperidin-1-ylmethyl.

The term “oxopyrrolydinylalkyl” denotes an alkyl wherein at least one ofthe hydrogen atoms of the alkyl has been replaced by an oxopyrrolydinylgroup. Particular example is 2-oxopyrrolydin-1-ylmethyl.

The present invention relates to a compound of formula (I)

whereinR¹ is selected from the group consisting of haloalkoxyalkyl,oxopyrrolydinylalkyl and oxopiperidinylalkyl; andR² is substituted phenyl or substituted pyridinyl, wherein substitutedphenyl and substituted pyridinyl are substituted with one to threesubstituents independently selected from the group consisting ofhaloalkyl, hydroxyhaloalkyl, alkoxy and haloalkoxy;or a pharmaceutically acceptable salt or ester thereof.

The term “pharmaceutically acceptable salts” refers to those salts whichretain the biological effectiveness and properties of the free bases orfree acids, which are not biologically or otherwise undesirable. Thesalts are formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and thelike, in particular hydrochloric acid, and organic acids such as aceticacid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleicacid, malonic acid, succinic acid, fumaric acid, tartaric acid, citricacid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid,N-acetylcystein and the like. In addition these salts may be prepared byaddition of an inorganic base or an organic base to the free acid. Saltsderived from an inorganic base include, but are not limited to, thesodium, potassium, lithium, ammonium, calcium, magnesium salts and thelike. Salts derived from organic bases include, but are not limited tosalts of primary, secondary, and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines andbasic ion exchange resins, such as isopropylamine, trimethylamine,diethylamine, triethylamine, tripropylamine, ethanolamine, lysine,arginine, N-ethylpiperidine, piperidine, polyimine resins and the like.Particular pharmaceutically acceptable salts of compounds of formula (I)are the hydrochloride salts, methanesulfonic acid salts and citric acidsalts.

“Pharmaceutically acceptable esters” means that compounds of generalformula (I) may be derivatised at functional groups to providederivatives which are capable of conversion back to the parent compoundsin vivo. Examples of such compounds include physiologically acceptableand metabolically labile ester derivatives, such as methoxymethylesters, methylthiomethyl esters and pivaloyloxymethyl esters.Additionally, any physiologically acceptable equivalents of thecompounds of general formula (I), similar to the metabolically labileesters, which are capable of producing the parent compounds of generalformula (I) in vivo, are within the scope of this invention.

The term “protecting group” (PG) denotes the group which selectivelyblocks a reactive site in a multifunctional compound such that achemical reaction can be carried out selectively at another unprotectedreactive site in the meaning conventionally associated with it insynthetic chemistry. Protecting groups can be removed at the appropriatepoint. Exemplary protecting groups are amino-protecting groups,carboxy-protecting groups or hydroxy-protecting groups. Particularprotecting groups are the tert-butoxycarbonyl (Boc), benzyloxycarbonyl(Cbz), fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn). Furtherparticular protecting groups are the tert-butoxycarbonyl (Boc) and thefluorenylmethoxycarbonyl (Fmoc). More particular protecting group is thebenzyl group (Bn).

The compounds of formula (I) can contain several asymmetric centers andcan be present in the form of optically pure enantiomers, mixtures ofenantiomers such as, for example, racemates, optically purediastereioisomers, mixtures of diastereoisomers, diastereoisomericracemates or mixtures of diastereoisomeric racemates.

According to the Cahn-Ingold-Prelog Convention the asymmetric carbonatom can be of the “R” or “S” configuration.

Also an embodiment of the present invention are compounds according toformula (I) as described herein and pharmaceutically acceptable salts oresters thereof, in particular compounds according to formula (I) asdescribed herein and pharmaceutically acceptable salts thereof, moreparticularly compounds according to formula (I) as described herein.

A further embodiment of the present invention are compounds according toformula (I) as described herein, wherein R¹ is haloalkoxyalkyl oroxopyrrolydinylalkyl.

A particular embodiment of the present invention are compounds accordingto formula (I) as described herein, wherein R¹ is haloalkoxyalkyl.

In a further embodiment of the present invention are compounds accordingto formula (I) as described herein, wherein R¹ is selected from thegroup consisting of 2-fluoroethoxymethyl, 2,2-difluoroethoxymethyl and2,2,2-trifluoroethoxymethyl.

Another further embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein R¹ is2-fluoroethoxymethyl or 2,2-difluoroethoxymethyl.

Another embodiment of the present invention are compounds according toformula (I) as described herein, wherein R¹ is 2-fluoroethoxymethyl.

The present invention also relates to compounds according to formula (I)as described herein, wherein R¹ is 2,2-difluoroethoxymethyl.

A further particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein R¹ is2,2,2-trifluoroethoxymethyl.

A more particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein R¹ isoxopyrrolydinylalkyl.

Also an embodiment of the present invention are compounds according toformula (I) as described herein, wherein R¹ is2-oxopyrrolydin-1-ylmethyl.

The present invention also relates to compounds according to formula (I)as described herein, wherein R¹ is oxopiperidinylalkyl.

Another embodiment of the present invention are compounds according toformula (I) as described herein, wherein R¹ is2-oxopiperidin-1-ylmethyl.

A further particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein R¹ is selectedfrom the group consisting of 2-fluoroethoxymethyl,2,2-difluoroethoxymethyl, 2,2,2-trifluoroethoxymethyl,2-oxopyrrolydin-1-ylmethyl and 2-oxopiperidin-1-ylmethyl.

A particular embodiment of the present invention are compounds accordingto formula (I) as described herein, wherein R¹ is selected from thegroup consisting of 2-fluoroethoxymethyl, 2,2-difluoroethoxymethyl and2-oxopyrrolydin-1-ylmethyl.

Also an embodiment of the present invention are compounds according toformula (I) as described herein, wherein R² is substituted phenyl orsubstituted pyridinyl, wherein substituted phenyl and substitutedpyridinyl are substituted with one to three substituents independentlyselected from the group consisting of alkoxy and haloalkoxy.

The present invention also relates to compounds according to formula (I)as described herein, wherein R² is substituted phenyl or substitutedpyridinyl, wherein substituted phenyl and substituted pyridinyl aresubstituted with one substituent selected from the group consisting oftrifluoromethyl, 2,2,2-trifluoro-1-hydroxyethyl, isopropoxy and1,1,1-trifluoropropan-2-yloxy.

Also an embodiment of the present invention are compounds according toformula (I) as described herein, wherein R² is substituted phenyl,wherein substituted phenyl is substituted with one to three substituentsindependently selected from the group consisting of haloalkyl,hydroxyhaloalkyl, alkoxy and haloalkoxy.

Another embodiment of the present invention are compounds according toformula (I) as described herein, wherein R² is substituted phenyl,wherein substituted phenyl is substituted with one substituent selectedfrom the group consisting of haloalkyl, hydroxyhaloalkyl, alkoxy andhaloalkoxy.

The present invention also relates to compounds according to formula (I)as described herein, wherein R² is substituted phenyl, whereinsubstituted phenyl is substituted with one substituent selected from thegroup consisting of trifluoromethyl, 2,2,2-trifluoro-1-hydroxyethyl,isopropoxy and 1,1,1-trifluoropropan-2-yloxy.

Also an embodiment of the present invention are compounds according toformula (I) as described herein, wherein R² is substituted phenyl,wherein substituted phenyl is substituted with one substituent selectedfrom the group consisting of isopropoxy and1,1,1-trifluoropropan-2-yloxy.

Also an embodiment of the present invention are compounds according toformula (I) as described herein, wherein R² is 4-(isopropoxy)phenyl or4-(1,1,1-trifluoropropan-2-yloxy)phenyl.

Another embodiment of the present invention are compounds according toformula (I) as described herein, wherein R² is substituted phenyl,wherein substituted phenyl is substituted with one haloalkyl.

A particular embodiment of the present invention are compounds accordingto formula (I) as described herein, wherein R² is4-(trifluoromethyl)phenyl.

A further particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein R² is substitutedphenyl, wherein substituted phenyl is substituted with onehydroxyhaloalkyl.

Also an embodiment of the present invention are compounds according toformula (I) as described herein, wherein R² is4-(2,2,2-trifluoro-1-hydroxyethyl)phenyl.

Another embodiment of the present invention are compounds according toformula (I) as described herein, wherein R² is substituted phenyl,wherein substituted phenyl is substituted with one alkoxy.

A particular embodiment of the present invention are compounds accordingto formula (I) as described herein, wherein R² is 4-(isopropoxy)phenyl.

A further particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein R² is substitutedphenyl, wherein substituted phenyl is substituted with one haloalkoxy.

The present invention also relates to compounds according to formula (I)as described herein, wherein R² is4-(1,1,1-trifluoropropan-2-yloxy)phenyl.

Another embodiment of the present invention are compounds according toformula (I) as described herein, wherein R² is substituted pyridinyl,wherein substituted pyridinyl is substituted with one to threesubstituents independently selected from the group consisting ofhaloalkyl, hydroxyhaloalkyl, alkoxy and haloalkoxy.

A further particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein R² is substitutedpyridinyl, wherein substituted pyridinyl is substituted with onesubstituent selected from alkoxy and haloalkoxy.

The present invention also relates to compounds according to formula (I)as described herein, wherein R² is substituted pyridinyl, whereinsubstituted pyridinyl is substituted with one substituent selected fromisopropoxy and 1,1,1-trifluoropropan-2-yloxy.

A particular embodiment of the present invention are compounds accordingto formula (I) as described herein, wherein R² is6-isopropoxypyridin-3-yl.

Another embodiment of the present invention are compounds according toformula (I) as described herein, wherein R² is6-(1,1,1-trifluoropropan-2-yloxy)pyridin-3-yl.

A further embodiment of the present invention are compounds according toformula (I) as described herein of formula (Ia)

Also a further embodiment of the present invention are compoundsaccording to formula (I) as described herein of formula (Ib)

Particular examples of compounds of formula (I) as described herein areselected from the group consisting of:

-   (5α,8α)-8-hydroxy-8-((2-oxopyrrolidin-1-yl)methyl)-2-(4-(trifluoromethyl)phenyl)-2-azaspiro[4.5]decan-1-one-   (5α,8α)-8-Hydroxy-8-(2-oxo-piperidin-1-ylmethyl)-2-(4-trifluoromethyl-phenyl)-2-aza-spiro[4.5]decan-1-one-   (5α,8α)-8-hydroxy-2-(4-isopropoxyphenyl)-8-((2-oxopyrrolidin-1-yl)methyl)-2-azaspiro[4.5]decan-1-one-   (5α,8α)-8-hydroxy-2-(4-isopropoxyphenyl)-8-((2-oxopiperidin-1-yl)methyl)-2-azaspiro[4.5]decan-1-one-   (5α,8α)-8-(2,2-Difluoro-ethoxymethyl)-8-hydroxy-2-(4-isopropoxy-phenyl)-2-aza-spiro[4.5]decan-1-one-   (5α,8α)-8-Hydroxy-2-(6-isopropoxy-pyridin-3-yl)-8-(2-oxo-pyrrolidin-1-ylmethyl)-2-aza-spiro[4.5]decan-1-one-   (5α,8α)-8-hydroxy-2-(6-isopropoxypyridin-3-yl)-8-(2,2,2-trifluoroethoxy)methyl)-2-azaspiro[4.5]decan-1-one-   (5α,8α)-8-Hydroxy-8-(2-oxo-pyrrolidin-1-ylmethyl)-2-[4-((R)-2,2,2-trifluoro-1-hydroxy-ethyl)-phenyl]-2-aza-spiro[4.5]decan-1-one-   (5α,8α)-8-hydroxy-8-((2-oxopyrrolidin-1-yl)methyl)-2-(4-((R)-1,1,1-trifluoropropan-2-yloxy)phenyl)-2-azaspiro[4.5]decan-1-one-   (5α,8α)-8-hydroxy-8-((2-oxopyrrolidin-1-yl)methyl)-2-(6-((S)-1,1,1-trifluoropropan-2-yloxy)pyridin-3-yl)-2-azaspiro[4.5]decan-1-one-   (5α,8α)-8-(2-fluoroethoxy)methyl)-8-hydroxy-2-(6-((S)-1,1,1-trifluoropropan-2-yloxy)pyridin-3-yl)-2-azaspiro[4.5]decan-1-one-   (5α,8α)-8-(2-fluoroethoxy)methyl)-8-hydroxy-2-(4-isopropoxyphenyl)-2-azaspiro[4.5]decan-1-one;    and pharmaceutically acceptable salts thereof.

Further particular examples of compounds of formula (I) as describedherein are selected from the group consisting of:

-   (5α,8α)-8-hydroxy-2-(4-isopropoxyphenyl)-8-((2-oxopyrrolidin-1-yl)methyl)-2-azaspiro[4.5]decan-1-one;-   (5α,8α)-8-(2,2-Difluoro-ethoxymethyl)-8-hydroxy-2-(4-isopropoxy-phenyl)-2-aza-spiro[4.5]decan-1-one;-   (5α,8α)-8-(2-fluoroethoxy)methyl)-8-hydroxy-2-(6-((S)-1,1,1-trifluoropropan-2-yloxy)pyridin-3-yl)-2-azaspiro[4.5]decan-1-one;    and pharmaceutically acceptable salts thereof.

Processes for the manufacture of compounds of formula (I) as describedherein are an object of the invention.

The preparation of compounds of formula (I) of the present invention maybe carried out in sequential or convergent synthetic routes. Synthesesof the invention are shown in the following general schemes. The skillsrequired for carrying out the reaction and purification of the resultingproducts are known to those persons skilled in the art. In case amixture of enantiomers or diastereoisomers is produced during areaction, these enantiomers or diastereoisomers can be separated bymethods described herein or known to the man skilled in the art such ase.g. chiral chromatography or crystallization. The substituents andindices used in the following description of the processes have thesignificance given herein. A relative configuration [5α,8α] on the8-hydroxy-2-aza-spiro[4.5]decan-1-one backbone corresponds to cisconfiguration on the cyclohexane ring, whereas a relative configuration[5α,8β] corresponds to a trans configuration on the cyclohexane ring ofcompounds according to formula (I) as described above.

Compounds of formula (I) are readily accessible as outlined in scheme 1by treating compounds of formula A8 with compounds of formula R¹—H asdefined above in the presence of a base such as sodium hydride orpotassium tert-butoxide in a solvent such as DMF, THF or tert-butanol orthe like at a temperature comprised between RT and reflux.

The compounds of formula R¹—H are either commercially available ordescribed in the literature. The synthesis of intermediates of formulaA8 are outlined in Schemes 2 and 3.

Thus, as outlined in scheme 2, commercially available ketone A1 can beprotected for example as a ketal (step (a)) to give the compound A2according to methods known in the literature. Ketal A2 is then alkylatedat the appropriate position by treatment with a suitable base such aslithium diisopropylamide, lithium or sodium hexamethyldisilazane,potassium tert-butoxide or the like in an appropriate solvent such asTHF, DMF, diethylether or the like followed by addition of theappropriate electrophile such as 1-bromo-2-methoxyethane to givecompound A3 (step (b)). A3 can be isolated if desired or the ketal groupcan be removed (step (c)) during the workup of reaction step (b). Thus,treatment of crude A3 with a strong aqueous mineral acid such as HCl,H₂SO₄, HBr or the like at various temperatures ranging from −15° C. to100° C. until hydrolysis of the ketal protecting group is completed(step (c)) gives compound A4.

Reduction of compound A4 (step (d)) can be accomplished with reducingagents such as NaBH₄ or similar in an appropriate solvent such as MeOH,EtOH or 2-propanol at 0° C. or elevated temperatures giving rise tocompound A5 as mixtures of cis and trans isomers.

Subsequent transformation to compounds of formula A6 (as a mixture ofcis/trans isomers) can be achieved according to Scheme 2 (step (e)) bytreatment of A5 (as a mixture of cis/trans isomers) with appropriatecompounds of formula R²—NH₂ and an appropriate organometallic reagentsuch as (CH₃)₂AlCl or Al(CH₃)₃, in an appropriate solvent such astoluene, benzene, chloroform, dioxane or the like at a suitabletemperature ranging from 0 to 150° C. to provide compounds of formulaA6.

Subsequent oxidation of compounds of formula A6 can be achieved asoutlined in Scheme 2, (step (h)), with various oxidizing agents such asoxalyl chloride/DMSO/amine base, TEMPO/NaOCl, TPAP/NMO, Jones reagent ormany more under the appropriate conditions and temperatures and gives tocompound of general formula A7. Subsequent epoxidation of A7 with e.g.trimethylsulfoxonium iodide in the presence of potassium tert-butoxidein DMSO as solvent (step (g)) gives then rise to compounds A8, as amixture of the cis or (3α,6α) isomer and the trans or (3α,6β)respectively, readily separable from the mixture by chromatography orcrystallization.

An alternative process to synthesize compounds A8 is described in scheme3.

Starting from intermediate A2, this is alkylated with anα-haloacetonitrile in the presence of a suitable base such as LDA, NaHor the like in an appropriate solvent such as THF, diethylether orsimilar, with or without addition of HMPA, to provide compound A9 (step(h)). A9 is then further transformed to the lactam A10 by reduction ofthe nitrile group to the primary amine by, for example, catalytichydrogenation with Raney-Ni as catalyst in NH3-EtOH as solvent andsubsequent heating of the intermediate in toluene in the presence of abase such as triethylamine to achieve the ring closure reaction (step(i)).

Compounds of formula A11 can then be prepared from A10 and compounds offormula R²—X, wherein X is halogen by making use of a Buchwald typecopper- or palladium-catalysed coupling reaction (Buchwald et al. JACS,2002, 124, p 7421). Suitable conditions for such reactions are forexample: CuI and, for example, N,N′-dimethylethylenediamine as ligandand K₃PO₄ as base in a solvent such as DMF or with palladium(II) acetateas catalyst and, for example, bis(diphenylphosphino)-ferrocene (DPPF) asligand, sodium tert-butoxide as a base in a solvent such as toluene.

Subsequently, compounds A11 can be converted to compounds A7 by acidichydrolysis, for example by treatment with an aqueous mineral acid suchas HCl, H₂SO₄ or the like (step (k)). The compounds of formula R²—X areeither commercial, known in the literature or were prepared followinggeneral synthetic procedures described in the art. Conversion of A7 toA8 is then accomplished as already described in scheme 2.

Also an embodiment of the present invention is a process to prepare acompound of formula (I) as defined above comprising the reaction of acompound of formula (II) in the presence of compound of formula (III);

In particular in presence of a base, particularly sodium hydride andpotassium tert-butoxide, in a solvent, particularly DMF, THF andtert-butanol, at a temperature comprised between RT and reflux, whereinR¹ and R² are as defined herein.

Also an object of the present invention is a compound according toformula (I) as described herein for use as therapeutically activesubstance.

Likewise an object of the present invention is a pharmaceuticalcomposition comprising a compound according to formula (I) as describedherein and a therapeutically inert carrier.

Also an object of the present invention is the use of a compoundaccording to formula (I) as described herein for the treatment orprophylaxis of illnesses which are caused by disorders associated withthe enzyme hormone-sensitive lipase.

The present invention relates to the use of a compound according toformula (I) as described above for the treatment or prophylaxis ofdiabetes, metabolic syndrome, dyslipidemia, atherosclerosis, obesity,cardiovascular diseases, myocardial dysfunction, inflammation,nonalkoholic fatty liver disease or nonalkoholic steatohepatitis

The present invention particularly relates to the use of a compoundaccording to formula (I) as described above for the treatment orprophylaxis of diabetes, metabolic syndrome, dyslipidemia,atherosclerosis or obesity.

A particular embodiment of the present invention is the use of acompound according to formula (I) as described above for the treatmentor prophylaxis of diabetes.

A further particular embodiment of the present invention is the use of acompound according to formula (I) as described above for the treatmentor prophylaxis of diabetes Type II.

Also an embodiment of the present invention is the use of a compoundaccording to formula (I) as described above for the treatment orprophylaxis of cardiovascular diseases, myocardial dysfunction,inflammation, nonalkoholic fatty liver disease or nonalkoholicsteatohepatitis.

A particular embodiment of the present invention is the use of acompound according to formula (I) as described above for the treatmentor prophylaxis of nonalkoholic fatty liver disease or nonalkoholicsteatohepatitis.

The present invention also relates to the use of a compound according toformula (I) as described above for the preparation of a medicament forthe treatment or prophylaxis of diabetes, metabolic syndrome,dyslipidemia, atherosclerosis, obesity, cardiovascular diseases,myocardial dysfunction, inflammation, nonalkoholic fatty liver diseaseor nonalkoholic steatohepatitis.

The present invention particularly relates to the use of a compoundaccording to formula (I) as described above for the preparation of amedicament for the treatment or prophylaxis of diabetes, metabolicsyndrome, dyslipidemia, atherosclerosis or obesity.

A particular embodiment of the present invention is the use of acompound according to formula (I) as described above for the preparationof medicaments for the treatment or prophylaxis of diabetes.

A further particular embodiment of the present invention is the use of acompound according to formula (I) as described above for the preparationof medicaments for the treatment or prophylaxis of diabetes Type II.

Also an embodiment of the present invention is the use of a compoundaccording to formula (I) as described above for the preparation of amedicament for the treatment or prophylaxis of cardiovascular diseases,myocardial dysfunction, inflammation, nonalkoholic fatty liver diseaseor nonalkoholic steatohepatitis.

A particular embodiment of the present invention is the use of acompound according to formula (I) as described above for the preparationof a medicament for the treatment or prophylaxis of nonalkoholic fattyliver disease or nonalkoholic steatohepatitis.

The present invention particularly relates to a compound according toformula (I) as described above for the treatment or prophylaxis ofdiabetes, metabolic syndrome, dyslipidemia, atherosclerosis, obesity,cardiovascular diseases, myocardial dysfunction, inflammation,nonalkoholic fatty liver disease or nonalkoholic steatohepatitis.

A particular embodiment of the present invention is a compound accordingto formula (I) as described above for the treatment or prophylaxis ofdiabetes, metabolic syndrome, dyslipidemia, atherosclerosis or obesity.

A further particular embodiment of the present invention is a compoundaccording to formula (I) as described above for the treatment orprophylaxis of diabetes.

Also a further particular embodiment of the present invention is acompound according to formula (I) as described above for the treatmentor prophylaxis of diabetes Type II.

Also a particular embodiment of the present invention is a compoundaccording to formula (I) as described above for the treatment orprophylaxis of cardiovascular diseases, myocardial dysfunction,inflammation, nonalkoholic fatty liver disease or nonalkoholicsteatohepatitis.

A further particular embodiment of the present invention is a compoundaccording to formula (I) as described above for the treatment orprophylaxis of nonalkoholic fatty liver disease or nonalkoholicsteatohepatitis.

Also an object of the invention is a method for the treatment orprophylaxis of diabetes, metabolic syndrome, dyslipidemia,atherosclerosis, obesity, cardiovascular diseases, myocardialdysfunction, inflammation, nonalkoholic fatty liver disease ornonalkoholic steatohepatitis, which method comprises administering aneffective amount of a compound according to formula (I) as describedabove.

Also a particular object of the invention is a method for the treatmentor prophylaxis of diabetes, metabolic syndrome, dyslipidemia,atherosclerosis or obesity, which method comprises administering aneffective amount of a compound according to formula (I) as describedabove.

A particular embodiment of the present invention is a method for thetreatment or prophylaxis of diabetes, which method comprisesadministering an effective amount of a compound according to formula (I)as described above.

A further particular embodiment of the present invention is a method forthe treatment or prophylaxis of diabetes Type II, which method comprisesadministering an effective amount of a compound according to formula (I)as described above.

Also an embodiment of the present invention is a method for thetreatment or prophylaxis of cardiovascular diseases, myocardialdysfunction, inflammation, nonalkoholic fatty liver disease ornonalkoholic steatohepatitis, which method comprises administering aneffective amount of a compound according to formula (I) as describedabove.

Also a further embodiment of the present invention is a method for thetreatment or prophylaxis of nonalkoholic fatty liver disease ornonalkoholic steatohepatitis, which method comprises administering aneffective amount of a compound according to formula (I) as describedabove.

A further object of the present invention comprises a compound accordingto formula (I) as described herein, when manufactured according to anyone of the described processes.

Assay Procedures

Production of Human Full Length Hormone Sensitive Lipase-His⁶:

1) Cloning: cDNA was prepared from commercial human brain polyA+ RNA andused as a template in overlapping PCR to generate a full length humanHSL ORF with a 3′-His6 tag. This full length insert was cloned into thepFast-BAC vector and the DNA-sequence of several single clones wasverified. DNA from a correct full length clone with the 3′His6 tag wasused to transform the E. coli strain DH10BAC. Resulting bacmid DNA wasused to generate a titered baculovirus stock for protein generation. Thesequence of the encoded HSL conforms to Swissprot entry Q05469, with theadditional C-terminal His6-tag.2) Protein purification: Culture: 5.5 L, High 5 cells expressing humanfull length HSL-His⁶, 48 hr., containing 25 μM E−64. Cell count:1.78×10¹⁰ cells/ml, 90% viable.Cells were thawed. On ice, cells were suspended in Base Buffercontaining 10% glycerol, 25 mM Tris-Cl, 300 mM NaCl, 10 mM imidazole, 10mM 2-mercaptoethanol, 2 μg pepstatin/ml, 2 μg leupeptin/ml, 2 μgantipain/ml, pH 8.0 at 4° C. in a final volume of 475 ml with 3.75×107cells/ml. Sanitation was done at 3×30 sec., Lubrol PX was added to 0.2%final concentration followed by stirring for 15 min at 4° C. andcentrifugation at 25 k×g, 60 min, 4° C. Soluble proteins were mixed with60 ml of pre-washed and equilibrated Ni-NTA Agarose (Qiagen 30210)followed by tumbling end-over-end, 45 min., 4° C., centrifugation 1000rpm 5 min and letting resin settle 5 min. Supernatant was removed, theresin washed in the centrifuge vessel using 5 volumes of Base Buffercontaining 0.2% Lubrol PX. Centrifugation was done again, then thesupernatant discarded. The resin was poured onto a 0.8 μm membrane in adisposable filter unit (Nalge 450-0080), and washed with 5 volumes ofBase Buffer containing 0.2% Lubrol PX. It was then washed with 30volumes of Base Buffer containing 60 mM imidazole pH 7.5 at 4° C. Theprotein was eluated with 5 volumes of 25 mM Tris-Cl, 300 mM NaCl, 200 mMimidazole, 10 mM 2-mercaptoethanol, pH 7.5 at 4° C. by tumbling resinwith buffer end-over-end, 30 min., 4° C. The resin was captured on a 0.2μm membrane disposable filter unit (Millipore SCGP U02 RE) and theeluate collected in the reservoir. The eluate was concentrated using a30 k MWCO centrifugal filter device (Sartorius Vivascience Vivacell 100,VC1022), to 20 ml. It was then dialyzed overnight at 4° C., two timesagainst 2 L of 10% glycerol, 25 mM Tris-Cl, 300 mM NaCl, 0.2 mM EDTA,0.2 mM DTT, pH 7.5 at 4° C. The protein was filtered using a 0.22 μmdisposable filter unit (Millipore SCGP00525). The protein concentrationwas calculated from absorbance at 280 nm, using 280=0.67 cm⁻¹ mg-1.Yield was 235 mg, total. The protein was stored at −80° C.Human Hormone-Sensitive Lipase (HSL) Enzyme Inhibition Assay:

HSL enzyme activity was measured by a colorimetric assay using2,3-dimercapto-1-propanol tributyrate (Aldrich, St. Louis, Mo.) as asubstrate. Typically, 1.5 mM 2,3-dimercapto-1-propanol tributyrate(DMPT) in 100 mM MOPS, pH 7.2, 0.2 mg/ml fatty acid-free BSA wasprepared by sonication at 4° C. to homogenous suspension. Test compounds(2 mM stock in DMSO) were diluted 3 fold in series in DMSO. Compoundsolutions were diluted 24 fold in 1.5 mM DMPT containing solution and 18ul per well was added to 384-well microplates (Corning Costar). Twelvemicroliters per well of human HSL (15 ug/ml) was added and the reactionmixture was incubated at 37° C. for 20 minutes. Six microliters of 12 mMdithio-bis-(2-nitrobenzoic acid) (DTNB) in DMSO plus 1.2% SDS and 0.6%Triton X-100 were added and the mixture was incubated at roomtemperature for 15 minutes. Product production was monitored by readingabsorbance at 405 nm on an Envision Reader (PerkinElmer Life andAnalytical Sciences, Shelton, Conn.).

Cellular Assay:

The following assay was used to measure the effect of the compounds toinhibit lipolysis in intact cells (adipocytes).

3T3-L1 pre-adipocyte cells were plated into 96-well plates at a densityof 20,000 cells/well in 200 ul growth media (DMEM/10% Calf Serum/1×antibiotic-antimycotic) until confluent. At 48 hours post-confluency,the medium was removed and the cells were differentiated into adipocyteswith differentiation medium (DMEM/10% FBS/1× Antibiotic-AntimycoticPLUS: 1 uM IBMX (3-Isobutyl-1-methylxanthine) Inhibitor ofphosphodiesterases, 1 uM Dexamethasone, 1 uM Rosiglitazone, 10 ug/mlInsulin). The cells were incubated in said medium for 3 days and thenmedium was changed to post-differentiation medium (DMEM/10% FBS PLUS: 10ug/ml Insulin) and the cells were incubated for an additional 3 days.The medium was then changed to maintenance media (DMEM/10% FBS). Thecells were fed every 3 days with maintenance media until use. Thelipolysis assay may be performed on day 9-14 after the initiation ofdifferentiation in 96 well plates.

The lipolysis assay was performed as follows. The adipocytes were washed2× with 200 ul Krebs Ringer Bicarbonate Hepes buffer (KRBH)/3% BSA. Testcompounds were at 10 mM in DMSO and were initially diluted to 5 mM inDMSO. They were then serially diluted 5-fold in DMSO (5 mM to 320 pM).Each compound was then diluted 200-fold into KRBH/3% BSA (0.5% DMSOfinal). The resulting solutions range from 25 uM to 1.6 pM final. Onehundred fifty ul of the diluted compounds were added to each well (intriplicate) and the cells were preincubated 30 min at 37° C. Forskolin(50 uM final) was added to the wells and the cells were incubated 120minutes at 37° C. One hundred ul was collected into a new 96-well platefor glycerol analysis. The amount of glycerol produced was determinedusing a glycerol determination kit (Sigma).

HSL hum IC50 Examples (uM) 1 0.0077 2 0.0681 3 0.0509 4 0.0274 5 0.01636 0.264 7 0.0137 8 0.213 9 0.0306 10 0.0418 11 0.01 12 0.037

Compounds of formula (I) and their pharmaceutically acceptable salts oresters thereof as described above have IC₅₀ values between 0.0001 uM and1000 uM, particular compounds have IC₅₀ values between 0.001 uM and 500uM, further particular compounds have IC₅₀ values between 0.001 uM and 5uM. These results have been obtained by using the foregoing HSL enzymeinhibition assay (uM means microMolar).

The compounds of formula (I) and their pharmaceutically acceptable saltscan be used as medicaments (e.g. in the form of pharmaceuticalpreparations). The pharmaceutical preparations can be administeredinternally, such as orally (e.g. in the form of tablets, coated tablets,dragées, hard and soft gelatin capsules, solutions, emulsions orsuspensions), nasally (e.g. in the form of nasal sprays) or rectally(e.g. in the form of suppositories). However, the administration canalso be effected parentally, such as intramuscularly or intravenously(e.g. in the form of injection solutions).

The compounds of formula (I) and their pharmaceutically acceptable saltscan be processed with pharmaceutically inert, inorganic or organicadjuvants for the production of tablets, coated tablets, dragées andhard gelatin capsules. Lactose, corn starch or derivatives thereof,talc, stearic acid or its salts etc. can be used, for example, as suchadjuvants for tablets, dragées and hard gelatin capsules.

Suitable adjuvants for soft gelatin capsules, are, for example,vegetable oils, waxes, fats, semi-solid substances and liquid polyols,etc.

Suitable adjuvants for the production of solutions and syrups are, forexample, water, polyols, saccharose, invert sugar, glucose, etc.

Suitable adjuvants for injection solutions are, for example, water,alcohols, polyols, glycerol, vegetable oils, etc.

Suitable adjuvants for suppositories are, for example, natural orhardened oils, waxes, fats, semi-solid or liquid polyols, etc.

Moreover, the pharmaceutical preparations can contain preservatives,solubilizers, viscosity-increasing substances, stabilizers, wettingagents, emulsifiers, sweeteners, colorants, flavorants, salts forvarying the osmotic pressure, buffers, masking agents or antioxidants.They can also contain still other therapeutically valuable substances.

The dosage can vary in wide limits and will, of course, be fitted to theindividual requirements in each particular case. In general, in the caseof oral administration a daily dosage of about 0.1 mg to 20 mg per kgbody weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g.about 300 mg per person), divided into preferably 1-3 individual doses,which can consist, for example, of the same amounts, should beappropriate. It will, however, be clear that the upper limit givenherein can be exceeded when this is shown to be indicated. The inventionis illustrated hereinafter by Examples, which have no limitingcharacter.

In case the preparative examples are obtained as a mixture ofenantiomers, the pure enantiomers can be separated by methods describedherein or by methods known to the man skilled in the art, such as e.g.chiral chromatography or crystallization.

EXAMPLES Example 1(5α,8α)-8-hydroxy-8-((2-oxopyrrolidin-1-yl)methyl)-2-(4-(trifluoromethyl)phenyl)-2-azaspiro[4.5]decan-1-one

Step 1: 1,4-Dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester

Ethyl-cyclohexanone-4-carboxylate (54.8 g) was dissolved in toluene (120ml). Then, ethylene glycol (24.8 ml) and toluene-4-sulfonic acidmonohydrate (612 mg) were added to the reaction mixture. The mixture wasrefluxed over night and water was removed azeotropically with aDean-Stark apparatus. The reaction mixture was cooled, poured intoice/water and basified with 2M aqueous NaOH to pH 9. The aqueous layerwas extracted two times with ethyl acetate. The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered and the solvent wasevaporated. The residue was purified by flash chromatography (silicagel, gradient of heptane in ethyl acetate) to give the title compound asa light yellow liquid (39.5 g). MS (m/e)=215.3 [MH⁺].

Step 2: 8-Cyanomethyl-1,4-dioxa-spiro[4.5]decane-8-carboxylic acid ethylester

To a stirred solution of diisopropylamine (10.09 ml, 69.76 mmol) in THF(150 ml) was added nBuLi (1.9 M solution in hexane, 26.09 ml, 51.1 mmol)drop wise at −40° C. followed by HMPA (31.0 ml, 178.0 mmol) undernitrogen atmosphere, and the reaction mixture was stirred for 30 minutesat −40° C. It was then cooled further to −78° C., and a solution of1,4-dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester (10 g, 46.5mmol) in THF (20 ml) was added keeping the temperature below −70° C.throughout the addition. After stirring for 25 min at −78° C.,bromoacetonitrile (3.8 ml, 55.8 mmol) was added slowly, and the reactionmixture was then allowed to warm to 25° C. The mixture was poured intocold water (100 ml) and the aqueous layer was extracted with EtOAc (5×70ml). The combined organic layer was washed successively with saturatedaqueous solution of NH₄Cl (3×50 ml), H2O (2×50 ml) and then with brine(1×40 ml), dried (Na₂SO₄), filtered and evaporated in vacuo. The crudecompound obtained was purified by column chromatography over silica gel(22-25% EtOAc/hexane) to give the title compound (6 g) as a pale yellowliquid. MS (m/e): 254.2 [MH⁺].

Step 3: 1,4-Dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one

To a stirred solution of8-cyanomethyl-1,4-dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester(12 g, 47.3 mmol) in a mixture of NH₃-EtOH (200 ml, 7:93) was addedRaney-Ni (4.16 g, 70.95 mmol) under nitrogen atmosphere at 25° C. Thereaction mixture was then hydrogenated at 40° C. in an autoclave under400 psi H2 pressure for 16 h. After the completion of reaction, themixture was filtered through a bed of celite, and the filtrate wasevaporated under reduced pressure. The crude material thus obtained (10g, 38.9 mmol) was dissolved in dry toluene (100 ml) and to the stirredsolution was added Et₃N (10 ml, 71.14 mmol) under a nitrogen atmosphereat 25° C. The mixture was then heated under reflux for 24 h. After thecompletion of reaction, it was cooled to 25° C., the precipitated whitesolid was filtered, washed with hexane (3×50 ml), dried under vacuum togive the title compound (7.3 g) as a white solid. MS (m/e): 212.2 [MH⁺].

Step 4:10-(4-Trifluoromethyl-phenyl)-1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one

1,4-Dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one (4 g) was dissolved inDMF (189 ml) at RT under an argon atmosphere. Then,1-bromo-4-(trifluoromethyl)benzene (6.39 g),N,N′-dimethylethylenediamine (sym) (3.34 g), cuprous iodide (5.41 g) andK₃PO₄ (7.13 g) were added and the mixture was heated at 100° C. for 12hours. The reaction mixture was cooled to RT, filtered and saturatedaqueous NH₄Cl solution was added. The mixture was then extracted twicewith AcOEt, the combined organic layers were washed with brine, driedover Na₂SO₄, filtered and the solvent was evaporated off in vacuo. Thecrude product was purified by flash chromatography (silica gel, gradientof 0% to 25% of acetronitrile in CH₂Cl₂) to give the title compound aswhite crystalline solid (4 g). MS (m/e): 356.146 [MH⁺].

Step 5: 2-(4-Trifluoromethyl-phenyl)-2-aza-spiro[4.5]decane-1,8-dione

10-(4-Trifluoromethyl-phenyl)-1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one(6.7 g) was dissolved in tetrahydrofuran (189 ml) aqueous hydrochloricacid solution (2M, 94.3 ml) was added and the mixture was stirred for 12hours at RT. The reaction mixture was poured into ice/water andextracted twice with ethyl acetate. The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and the solvent wasevaporated to give the title compound as a colorless foam (4.9 g). MS(m/e): 311 [M⁺].

Step 6:(3α,6α)-8-(4-Trifluoromethyl-phenyl)-1-oxa-8-aza-dispiro[2.2.4.2]dodecan-7-one

2-(4-Trifluoromethyl-phenyl)-2-aza-spiro[4.5]decane-1,8-dione (4.9 g)and trimethylsulfoxonium iodide (5.37 g) were dissolved in DMSO (28.8ml). Then, a solution of potassium tert-butoxide (2.74 g) in DMSO (28.8ml) was added and the mixture was stirred at RT for 12 hours. Thereaction mixture was poured into ice/water and was extracted twice withethyl acetate. The combined organic layers were washed with brine, driedover Na₂SO₄ and filtered. The solvent was evaporated and the residue waspurified by flash chromatography (silica gel, gradient 0% to 50% AcOEtin heptane in) to give the title compound as a white solid (3.816 g). MS(m/e): 326.2 [MH⁺]

Step 7: (5α,8α)-8-hydroxy-8-((2-oxopyrrolidin-1-yl)methyl)-2-(4(trifluoromethyl)phenyl)-2-azaspiro[4.5]decan-1-one

To a suspension of sodium hydride (69.7 mg) in DMF (5.25 mL) at 0° C.was added under an argon atmosphere 2-pyrrolidone (52.3 mg) and thereaction mixture was stirred for 10 minutes. A solution of(3α,6α)-8-(4-trifluoromethyl-phenyl)-1-oxa-8-aza-dispiro[2.2.4.2]dodecan-7-one(200 mg, product of example 1 step 6) in DMF (2 ml) was added and thereaction mixture heated at 110° C. for 12 h. The reaction mixture waspoured into water, extracted with EtOAc, washed with brine and driedover Na₂SO₄ and concentrated in vacuo to give a crude residue which waspurified by flash column chromatography (silica gel, gradient of 0% to50% EtOAc in heptane) to yield the title compound as a white solid (113mg). MS (m/e): 411.188 (MH⁺).

Example 28-Hydroxy-8-(2-oxo-piperidin-1-ylmethyl)-2-(4-trifluoromethyl-phenyl)-2-aza-spiro[4.5]decan-1-one

The title compound was prepared in analogy to example 1 step 7 from(3α,6α)-8-(4-trifluoromethyl-phenyl)-1-oxa-8-aza-dispiro[2.2.4.2]dodecan-7-one(product of example 1 step 6) and 2-piperidinone as a white solid. MS(m/e): 425.204 [MH⁺].

Example 3(5α,8α)-8-hydroxy-2-(4-isopropoxyphenyl)-8-((2-oxopyrrolidin-1-yl)methyl)-2-azaspiro[4.5]decan-1-one

Step 1: 1,4-Dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester

Ethyl-cyclohexanone-4-carboxylate (54.8 g) was dissolved in toluene (120ml). Then, ethylene glycol (24.8 mL) and toluene-4-sulfonic acidmonohydrate (612 mg) were added to the reaction mixture. The mixture wasrefluxed over night and water was removed azeotropically with aDean-Stark apparatus. The reaction mixture was cooled, poured intoice/water and basified with 2M aqueous NaOH to pH 9. The aqueous layerwas extracted two times with ethyl acetate. The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered and the solvent wasevaporated. The residue was purified by flash chromatography (silicagel, gradient of heptane in ethyl acetate) to give the title compound asa light yellow liquid (39.5 g). MS (m/e)=215.3 [MH⁺].

Step 2: 1-(2-Methoxy-ethyl)-4-oxo-cyclohexanecarboxylic acid ethyl ester

A solution of 1,4-dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester(39.5 g) in THF (200 ml) was added dropwise over a period of 45 minutesat −5° C. (ice/methanol bath) to a solution of lithiumdiisopropylamide(2M in THF, 184.3 mL) in THF (300 ml). Stirring was continued for 2.5hours at 0° C. The reaction mixture was cooled to −5° C. and2-bromoethyl-methylether (34.6 ml) was added dropwise over a period of30 minutes. Stirring was continued for 12 hours at RT. The reactionmixture was cooled to 0° C. and aqueous HCl (25%, 300 ml) was addeddropwise over a period of 45 minutes to pH 1. Stirring was continued for2 hours at RT. The reaction mixture was poured into ice/water andextracted two times with ethyl acetate. The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and the solvent wasevaporated. The residue was purified by flash chromatography (silicagel, gradient of heptane in ethyl acetate) to give the title compound asa yellow liquid (25.2 g). MS (EI)=288.0 [M⁺].

Step 3: 4-1-(2-methoxy-ethyl)-cyclohexanecarboxylic acid ethyl ester

1-(2-Methoxy-ethyl)-4-oxo-cyclohexanecarboxylic acid ethyl ester (50 g)was dissolved in 2-propanol (400 ml). The mixture was cooled to 0° C.and sodium borohydride (10 g) was added in 8 portions over 20 minutes.Stirring was continued for 2 hours at 0° to 6° C. The reaction mixturewas partitioned between ice/water which was saturated with brine andethyl acetate, the layers were separated and the aqueous layer furtherextracted with AcOEt. The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered and the solvent was evaporated off.The title compound was obtained as a mixture of cis and transdiastereomeres (ratio: 3/1) as a yellow oil (41.7 g) and was usedwithout further purification. MS (EI)=230.0 [M⁺].

Step 4: 8-Hydroxy-2-(4-isopropoxy-phenyl)-2-aza-spiro[4.5]decan-1-one

4-Isopropoxy-phenylamine (11.3 g) was added to a solution of4-hydroxy-1-(2-methoxy-ethyl)-cyclohexanecarboxylic acid ethyl ester(11.5 g) in toluene (361 ml). The mixture was stirred for 10 minutes atRT. Then, dimethylaluminiumchloride (0.9 M in hexane, 99 ml) was addeddropwise and the reaction mixture was heated to reflux for 4 h. Themixture was then cooled to 0° C., water (50 ml) was added dropwise thenAcOEt (300 ml). The mixture was stirred further 30 minutes, more AcOEtwas added, the layers were then separated, the organic layer was driedover MgSO4, filtered and the solvent was evaporated off. The crudeproduct was triturated with diethyl ether/heptane to give the titlecompound as a mixture of cis/trans isomers as brown solid (14.3 g) whichwas used directly in the next step. MS (m/e): 304.190 [MH⁺].

Step 5: 2-(4-Isopropoxy-phenyl)-2-aza-spiro[4.5]decane-1,8-dione

To a solution of8-hydroxy-2-(4-isopropoxy-phenyl)-2-aza-spiro[4.5]decan-1-one (7 g) and2,2,6,6-tetramethylpiperidine-1-oxyl (721 mg) in dichloromethane (250ml) were added sequentially a solution of potassium bromide (549 mg) inwater (60 ml), sodium hypochlorite (52.8 ml), sodium bicarbonate (5.81g) and the reaction mixture was then stirred for 3 hour at RT. Thereaction mixture was poured into ice/water and extracted three timeswith CH₂Cl₂. The combined organic layers were washed with brine, driedover Na₂SO₄, filtered and the solvent was evaporated off. The residuewas purified by flash chromatography (silica gel, gradient 0% to 50%ethyl acetate in heptane) to give the title compound as a brown solid (5g). MS (m/e): 302.174 [MH⁺].

Step 6:(3α,6α)-8-(4-Isopropoxy-phenyl)-1-oxa-8-aza-dispiro[2.2.4.2]dodecan-7-one

2-(4-Isopropoxy-phenyl)-2-aza-spiro[4.5]decane-1,8-dione (3 g) andtrimethylsulfoxonium iodide (3.4 g) were dissolved in DMSO (72 ml).Then, a solution of potassium tert-butoxide (1.73 g) in DMSO (72 ml) wasadded and the mixture was stirred at RT for 12 hours. The reactionmixture was poured into ice/water and was extracted twice with ethylacetate. The combined organic layers were washed with brine, dried overNa₂SO₄ and filtered. The solvent was evaporated and the residue waspurified by flash chromatography (silica gel, gradient 0% to 50% AcOEtin heptane in) to give the title compound as a white solid (2.06 g). MS(m/e): 316.190 [MH⁺].

Step 7:(5α,8α)-8-hydroxy-2-(4-isopropoxyphenyl)-8-(2-oxopyrrolidin-1-yl)methyl)-2-azaspiro[4.5]decan-1-one

The title compound was prepared in analogy to example 1 step 7 from(3α,6α)-8-(4-isopropoxy-phenyl)-1-oxa-8-aza-dispiro[2.2.4.2]dodecan-7-oneand 2-pyrrolidone as an off white solid. MS (m/e): 401.242 [MH⁺].

Example 4(5α,8α)-8-Hydroxy-2-(4-isopropoxyphenyl)-8-((2-oxopiperidin-1-yl)methyl)-2-azaspiro[4.5]decan-1-one

The title compound was prepared in analogy to example 1 step 7 from(3α,6α)-8-(4-isopropoxy-phenyl)-1-oxa-8-aza-dispiro[2.2.4.2]dodecan-7-one(product of example 3 step 6) and 2-piperidinone as a white solid. MS(m/e): 415.258 [MH⁺].

Example 5(5α,8α)-8-(2,2-Difluoro-ethoxymethyl)-8-hydroxy-2-(4-isopropoxy-phenyl)-2-aza-spiro[4.5]decan-1-one

The title compound was prepared in analogy to example 1 step 7 from(3α,6α)-8-(4-isopropoxy-phenyl)-1-oxa-8-aza-dispiro[2.2.4.2]dodecan-7-one(product of example 3 step 6) and 2,2-difluoroethanol as a white solid.MS (m/e): 398.212 [MH⁺].

Example 6(5α,8α)-8-Hydroxy-2-(6-isopropoxy-pyridin-3-yl)-8-(2-oxo-pyrrolidin-1-ylmethyl)-2-aza-spiro[4.5]decan-1-one

Step 1:8-Hydroxy-2-(6-isopropoxy-pyridin-3-yl)-2-aza-spiro[4.5]decan-1-one

In analogy to example 3 step 4, from 6-isopropoxy-pyridin-3-ylamine(11.4 g), 4-hydroxy-1-(2-methoxy-ethyl)-cyclohexanecarboxylic acid ethylester (11.5 g) and dimethylaluminiumchloride (0.9 M in hexane, 99.9 ml)in toluene (360 ml) the title compound was obtained as mixture ofcis/trans isomers as a light red solid (7.49 g). MS (m/e): 305.2 [MH⁺].

Step 2: 2-(6-Isopropoxy-pyridin-3-yl)-2-aza-spiro[4.5]decane-1,8-dione

In analogy to example 3 step 5, by oxidation of8-hydroxy-2-(6-isopropoxy-pyridin-3-yl)-2-aza-spiro[4.5]decan-1-one (4.5g) the title compound (2.43 g) was obtained as yellow amorphous solid.MS (m/e): 303.169 [MH⁺].

Step 3:(3α,6α)-8-(6-Isopropoxy-pyridin-3-yl)-1-oxa-8-aza-dispiro[2.2.4.2]dodecan-7-one

In analogy to example 3 step 6, by epoxidation of2-(6-isopropoxy-pyridin-3-yl)-2-aza-spiro[4.5]decane-1,8-dione (2.5 g)the title compound (0.73 g) was obtained as yellow solid. MS (m/e):317.184 [MH⁺].

Step 4:(5α,8α)-8-Hydroxy-2-(6-isopropoxy-pyridin-3-yl)-8-(2-oxo-pyrrolidin-1-ylmethyl)-2-aza-spiro[4.5]decan-1-one

The title compound was prepared in analogy to example 1 step 7 from(3α,6α)-8-(6-isopropoxy-pyridin-3-yl)-1-oxa-8-aza-dispiro[2.2.4.2]dodecan-7-oneand 2-pyrrolidone as a light yellow solid. MS (m/e): 402.238 [MH⁺].

Example 7(5α,8α)-8-hydroxy-2-(6-isopropoxypyridin-3-yl)-8-((2,2,2-trifluoroethoxy)methyl)-2-azaspiro[4.5]decan-1-one

The title compound was prepared in analogy to example 1 step 7 from(3α,6α)-8-(6-isopropoxy-pyridin-3-yl)-1-oxa-8-aza-dispiro[2.2.4.2]dodecan-7-one,product of example 6 step 3, and 2,2,2-trifluoroethanol as an off whitesolid. MS (m/e): 417.199 [MH⁺].

Example 8(5α,8α)-8-Hydroxy-8-(2-oxo-pyrrolidin-1-ylmethyl)-2-[4-((R)-2,2,2-trifluoro-1-hydroxy-ethyl)-phenyl]-2-aza-spiro[4.5]decan-1-one

Step 1: 4-[(R)-1-(4-Bromo-phenyl)-2,2,2-trifluoro-ethoxymethyl]-phenol

(R)-1-(4-bromophenyl)-2,2,2-trifluoroethanol (3.5 g, synthesis describedin J. Org. Chem. 2009, 74, 1605-1610) was dissolved in THF (50 ml) underan argon atmosphere, NaH (719 mg) was added at 0° C. followed bytetrabutylammonium iodide (507 mg) then 4-methoxy-benzylbromide (3.04 g)and the mixture was stirred for 3.5 h at 20° C.

The reaction was quenched with water (15 ml) and then 1N aqueous HCl (15ml) was added followed by EtOAc (30 ml). The layers were separated andthe aqueous layer was extracted twice with EtOAc (each 30 ml). Thecombined aqueous layers were washed with brine, dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by flash chromatography(silica gel, gradient 0% to 25% ethyl acetate in heptane) to give thetitle compound as a white solid (4.7 g). ¹H-NMR (δ, CDCl₃): 7.55 (m,2H), 7.3 (m, 2H), 7.2 (m, 2H), 6.88 (m, 2H), 4.63 (d, 1H, J=11.5 Hz),4.58 (q, 1H, J=4.6 Hz), 4.38 (d, 1H, J=11.5 Hz), 3.82 (s, 3H).

Step 2:10-{4-[(R)-2,2,2-Trifluoro-1-(4-methoxy-benzyloxy)-ethyl]-phenyl}-1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one

The title compound was prepared in analogy to example 1 step 4 from1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one (2.05 g) (described inexample 1, step 3) and4-[(R)-1-(4-bromo-phenyl)-2,2,2-trifluoro-ethoxymethyl]-phenol (4.66 g)as a white solid (4.9 g) which was directly used in the next step.

Step 3:2-{4-[(R)-2,2,2-Trifluoro-1-(4-methoxy-benzyloxy)-ethyl]-phenyl}-2-aza-spiro[4.5]decane-1,8-dione

The title compound was prepared in analogy to example 1, step 5 from10-{4-[(R)-2,2,2-trifluoro-1-(4-methoxy-benzyloxy)-ethyl]-phenyl}-1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one(4.91 g) by treatment with 2 M HCl (58.3 ml) in THF (68.2 ml) as a whitesolid. (3.5 g).

Step 4:(3α,6α)-8-{4-[(R)-2,2,2-Trifluoro-1-(4-methoxy-benzyloxy)-ethyl]-phenyl}-1-oxa-8-aza-dispiro[2.2.4.2]dodecan-7-one

In analogy to example 1 step 6 by epoxidation of2-{4-[(R)-2,2,2-trifluoro-1-(4-methoxy-benzyloxy)-ethyl]-phenyl}-2-aza-spiro[4.5]decane-1,8-dione(2.5 g) the title compound (2 g) was obtained as yellow solid. MS (m/e):476.2 [MH⁺].

Step 5:(5α,8α)-8-Hydroxy-8-(2-oxo-pyrrolidin-1-ylmethyl)-2-{4-[(R)-2,2,2-trifluoro-1-(4-methoxy-benzyloxy)-ethyl]-phenyl}-2-aza-spiro[4.5]decan-1-one

To a solution of(3α,6α)-8-{4-[(R)-2,2,2-trifluoro-1-(4-methoxy-benzyloxy)-ethyl]-phenyl}-1-oxa-8-aza-dispiro[2.2.4.2]dodecan-7-on(250 mg) and pyrrolidin-2-one (58.2 mg) in a mixture of t-butylalcohol(5 ml) and THF (2 ml) was added potassium tert-butoxide (47.2 mg) andthe mixture was stirred at 80° C. for 12 h. The solvent was removed invacuo, the residue was taken up in EtOAc which was then washed withwater, brine and dried over MgSO₄. The solvent was evaporated off andthe residue was purified by flash chromatography (silica gel, gradient0% to 5% MeOH in methylen chloride) to give the title compound as awhite solid (134 mg). MS (m/e)=561.3 [MH⁺].

Step 6:(5α,8α)-8-Hydroxy-8-(2-oxo-pyrrolidin-1-ylmethyl)-2-[4-((R)-2,2,2-trifluoro-1-hydroxy-ethyl)-phenyl]-2-aza-spiro[4.5]decan-1-one

(5α,8α)-8-Hydroxy-8-(2-oxo-pyrrolidin-1-ylmethyl)-2-{4-[(R)-2,2,2-trifluoro-1-(4-methoxy-benzyloxy)-ethyl]-phenyl}-2-aza-spiro[4.5]decan-1-one(134 mg) was dissolved in methylene chloride (5 ml), water (0.25 ml) wasadded followed by DDQ (163 mg) and the reaction mixture was stirred for18 h at RT. The mixture was then partitioned between aqueous KHCO₃ andmethylene chloride, the layers were separated and the organic layer waswashed with aqueous KHCO₃ then with brine, dried over MgSO₄, filteredand concentrated in vacuo. The residue was purified by flashchromatography (silica gel, gradient 0% to 5% MeOH in methylen chloride)to give the title compound as a white solid (134 mg). MS (m/e)=441.3[MH⁺].

Example 9(5α,8α)-8-Hydroxy-8-((2-oxopyrrolidin-1-yl)methyl)-2-(4-((R)-1,1,1-trifluoropropan-2-yloxy)phenyl)-2-azaspiro[4.5]decan-1-one

Step 1: 4-((R)-2,2,2-Trifluoro-1-methyl-ethoxy)-phenylamine

Sodium hydride (55%, 3.22 g) was added to DMF (20 mL) and the mixturewas cooled to 0° C. Then, (R)-1,1,1-trifluoro-2-propanol (8.5 g) [CAS17628-73-8] was added over a period of 1 h and stirring was continuedfor 30 minutes at 0° C. A solution of 1-fluoro-4-nitro-benzene [CAS350-46-9] (10 g) in DMF (15 mL) was added over a period of 1.5 h whilethe internal temperature was kept between 5 to 15° C. Followingaddition, the mixture was allowed to warm to RT and stirring wascontinued for another 12 h. The reaction mixture was acidified andpartitioned between ethyl acetate and water. The organic layer wasseparated, dried over Na₂SO₄ and evaporated to dryness. The residue wasdissolved in methanol (150 ml) and Pd on carbon (10% Pd, 1 g) was added.The mixture was then hydrogenated at RT for 12 hours. The catalyst wasremoved by filtration and the filtrate was concentrated in vacuo toprovide crude 4-((R)-2,2,2-trifluoro-1-methyl-ethoxy)-phenylamine as adark liquid (14.5 g). MS (m/e): 206.1 (MH⁺).

Step 2:8-Hydroxy-2-[4-((R)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-2-aza-spiro[4.5]decan-1-one(mixture of cis and trans diastereomers)

4-((R)-2,2,2-Trifluoro-1-methyl-ethoxy)-phenylamine (7.57 g,) was addedto a solution of 4-hydroxy-1-(2-methoxy-ethyl)-cyclohexanecarboxylicacid ethyl ester (5.0 g, obtained in example 3, step 3) in toluene (150ml). The mixture was stirred for 10 minutes at RT. Then,dimethylaluminiumchloride (1M in hexane, 65.1 mL) was added dropwiseover a period of 45 minutes. The reaction mixture was heated to refluxfor 2 h and was then kept at 95° C. for 16 h. The mixture was cooled,poured into ice/water and extracted two times with ethyl acetate. Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and the solvent was evaporated. The title compound was obtainedas an mixture of cis and trans diastereomers as a light brown solid(5.79 g). This mixture was used without further purification. MS (m/e):358.3 [MH⁺].

Step 3:2-[4-((R)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-2-aza-spiro[4.5]decane-1,8-dione

To a solution of8-hydroxy-2-[4-((R)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-2-aza-spiro[4.5]decan-1-one(5.79 g) and 2,2,6,6-tetramethylpiperidine-1-oxyl radical (TEMPO) (506mg) in CH₂Cl₂ (85 ml) was added a solution of potassium bromide (482 mg)in water (16 mL). Then, sodiumhypochlorite (13%, 42.5 mL) was addeddropwise over a period of 10 minutes followed by sodium bicarbonate(NaHCO₃) (4.08 g). The mixture was stirred for 1.5 h at RT. TLC showed aremainder of starting material. More TEMPO (125 mg) andsodiumhypochlorite solution (10 mL) were added to the reaction mixtureand the mixture was stirred for additional 2 h at RT. The reactionmixture was poured into ice/water and was extracted three times withCH₂Cl₂. The combined organic layers were washed with brine, dried overNa₂SO₄, filtered and the solvent was evaporated. The crude material waspurified by flash chromatography (silica gel, gradient of heptane inethyl acetate) to provide the title compound as a light brown solid(5.47 g). MS (m/e): 356.1 (MH⁺).

Step 4:(3α,6α)-8-[4-((R)-2,2,2-Trifluoro-1-methyl-ethoxy)-phenyl]-1-oxa-8-aza-dispiro[2.2.4.2]dodecan-7-one

The title compound was prepared in analogy to example 3, step 6 byepoxidation of2-[4-((R)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-2-aza-spiro[4.5]decane-1,8-dione.MS (m/e): 370.2 [MH⁺].

Step 5:(5α,8α)-8-Hydroxy-8-((2-oxopyrrolidin-1-yl)methyl)-2-(4-((R)-1,1,1-trifluoropropan-2-yloxy)phenyl)-2-azaspiro[4.5]decan-1-one

The title compound was prepared in analogy to example 1 step 7 from(3α,6α)-2-[4-((R)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-2-aza-spiro[4.5]decane-1,8-dioneand 2-pyrrolidinone as a light yellow solid. MS (m/e): 445.214 [MH⁺].

Example 10(5α,8α)-8-Hydroxy-8-((2-oxopyrrolidin-1-yl)methyl)-2-(6-((S)-1,1,1-trifluoropropan-2-yloxy)pyridin-3-O-2-azaspiro[4.5]decan-1-one

Step 1: 5-Nitro-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine

In a 4-neck flask, commercially available 2-chloro-5-nitropyridine (71.9g) and (S)-1,1,1-trifluoropropan-2-ol (54.3 g) were dissolved in DMF(610 ml) and sodium hydride (20 g, 55%) was added at a temperature of 16to 18° C. (ice cooling). Following addition, the mixture was allowed tostir for 1 hour. The mixture was poured into ice and was allowed tohydrolyze. The suspension was warmed to RT over a period of 12 hours andthe solid was filtered and washed with additional water and then with asmall amount of hexanes (50 mL). The brown solid was further dried invacuo to provide the title compound. (81.9 g). ¹H-NMR (δ, CDCl₃): 9.06(m, 1H), 8.43 (dd, 1H), 6.93 (d, 1H), 5.87 (m, 1H); 1.54 (m, 3H).

Step 2: 6-((S)-2,2,2-Trifluoro-1-methyl-ethoxy)-pyridin-3-ylamine

5-Nitro-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine (81.9 g) andpalladium on carbon (10% Pd, 0.0065 mol-eq) were added to MeOH and themixture was hydrogenated until uptake of hydrogen was ceasing. Thecatalyst was removed by filtration and the filtrate was concentrated andfurther dried in vacuo to provide the title compound as a dark oil. MS(m/e): 207.0 (MH⁺).

Step 3:8-Hydroxy-2-[6-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridin-3-yl]-2-aza-spiro[4.5]decan-1-one

The title compound was obtained in analogy to example 3 step 4 from6-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridin-3-ylamine (23.3 g) and4-hydroxy-1-(2-methoxy-ethyl)-cyclohexanecarboxylic acid ethyl ester (20g, obtained in example 3, step 3) as a brown oil (39.3 g). MS (m/e):359.3 (MH⁺).

Step 4:2-[6-((S)-2,2,2-Trifluoro-1-methyl-ethoxy)-pyridin-3-yl]-2-aza-spiro[4.5]decane-1,8-dione

DMSO (16.3 ml) was added dropwise over a period of 5 minutes to asolution of8-hydroxy-2-[6-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridin-3-yl]-2-aza-spiro[4.5]decan-1-one(39.3 g) in dichloromethane (400 ml) that was cooled down to −78° C. ina CO₂/acetone-bath. After 5 minutes, oxalylchloride (15.6 ml) was addeddropwise over a period of 15 minutes and stirring was continued for 30minutes at −78° C. Then, triethylamine (42.7 ml) was added dropwise overa period of 15 minutes to the reaction mixture and after 5 minutes, themixture was allowed to warm to 20° C. and stirred further 2 h at R.T.The reaction mixture was poured into ice/water and was acidified with 2Maqueous HCl solution to pH 3. The aqueous phase was extracted two timeswith dichloromethane and the combined organic layers were washed withbrine, dried over Na₂SO₄ and filtered. The solvent was evaporated andthe residue was purified by flash chromatography (silica gel, gradient20% to 60 of AcOEt in hexane) to give the title compound as an off whitesolid (23.96 g). MS (m/e): 357.2 (MO.

Step 5:(3α,6α)-8-[6-((S)-2,2,2-Trifluoro-1-methyl-ethoxy)-pyridin-3-yl]-1-oxa-8-aza-dispiro[2.2.4.2]dodecan-7-one

The title compound was prepared in analogy to example 3, step 6 from2-[6-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridin-3-yl]-2-aza-spiro[4.5]decane-1,8-dioneas an off-white solid. MS (m/e): 371.3 [MH⁺].

Step 6:(5α,8α)-8-Hydroxy-8-((2-oxopyrrolidin-1-yl)methyl)-2-(6-((S)-1,1,1-trifluoropropan-2-yloxY)pyridin-3-yl)-2-azaspiro[4.5]decan-1-one

The title compound was prepared in analogy to example 1, step 7 from(3α,6α)-8-[6-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridin-3-yl]-1-oxa-8-aza-dispiro[2.2.4.2]dodecan-7-oneand 2-pyrrolidinone as an off white solid. MS (m/e): 445.210 [MH⁺].

Example 11(5α,8α)-8-((2-Fluoroethoxy)methyl)-8-hydroxy-2-(6-((S)-1,1,1-trifluoropropan-2-yloxy)pyridin-3-yl)-2-azaspiro[4.5]decan-1-one

The title compound was prepared in analogy to example 8, step 5 from(3α,6α)-8-[6-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridin-3-yl]-1-oxa-8-aza-dispiro[2.2.4.2]dodecan-7-oneand 2-fluorethanol as an off white solid. MS (m/e): 435.189 [MH⁺].

Example 12(5α,8α)-8-((2-fluoroethoxy)methyl)-8-hydroxy-2-(4-isopropoxyphenyl)-2-azaspiro[4.5]decan-1-one

The title compound was prepared in analogy to example 8, step 5 from(3α,6α)-8-(4-isopropoxy-phenyl)-1-oxa-8-aza-dispiro[2.2.4.2]dodecan-7-one(prepared in example 3 step 6) and 2-fluorethanol as a brown solid. MS(m/e): 380.224 [MH⁺].

Example A

A compound of formula (I) can be used in a manner known per se as theactive ingredient for the production of tablets of the followingcomposition:

Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mgCorn starch  25 mg Talc  25 mg Hydroxypropylmethylcellulose  20 mg 425mg

Example B

A compound of formula (I) can be used in a manner known per se as theactive ingredient for the production of capsules of the followingcomposition:

Per capsule Active ingredient 100.0 mg Corn starch  20.0 mg Lactose 95.0 mg Talc  4.5 mg Magnesium stearate  0.5 mg 220.0 mg

The invention claimed is:
 1. A compound according to formula (I),

wherein R¹ is selected from the group consisting of haloalkoxyalkyl,oxopyrrolydinylalkyl and oxopiperidinylalkyl; and R² is substitutedphenyl or substituted pyridinyl, wherein substituted phenyl andsubstituted pyridinyl are substituted with one to three substituentsindependently selected from the group consisting of haloalkyl,hydroxyhaloalkyl, alkoxy and haloalkoxy; or a pharmaceuticallyacceptable salt or ester thereof.
 2. A compound according to claim 1,wherein R¹ is haloalkoxyalkyl or oxopyrrolydinylalkyl.
 3. A compoundaccording to claim 1, wherein R¹ is haloalkoxyalkyl.
 4. A compoundaccording to claim 1, wherein R¹ is selected from the group consistingof 2-fluoroethoxymethyl, 2,2-difluoroethoxymethyl and2,2,2-trifluoroethoxymethyl.
 5. A compound according to claim 1, whereinR¹ is 2-fluoroethoxymethyl or 2,2-difluoroethoxymethyl.
 6. A compoundaccording to claim 1, wherein R¹ is 2-fluoroethoxymethyl.
 7. A compoundaccording to claim 1, wherein R¹ is 2,2-difluoroethoxymethyl.
 8. Acompound according to claim 1, wherein R¹ is2,2,2-trifluoroethoxymethyl.
 9. A compound according to claim 1, whereinR¹ is oxopyrrolydinylalkyl.
 10. A compound according to claim 1, whereinR¹ is 2-oxopyrrolydin-1-ylmethyl.
 11. A compound according to claim 1,wherein R¹ is oxopiperidinylalkyl.
 12. A compound according to claim 1,wherein R¹ is 2-oxopiperidin-1-ylmethyl.
 13. A compound according toclaim 1, wherein R¹ is selected from the group consisting of2-fluoroethoxymethyl, 2,2-difluoroethoxymethyl,2,2,2-trifluoroethoxymethyl, 2-oxopyrrolydin-1-ylmethyl and2-oxopiperidin-1-ylmethyl.
 14. A compound according to claim 1, whereinR¹ is selected from the group consisting of 2-fluoroethoxymethyl,2,2-difluoroethoxymethyl and 2-oxopyrrolydin-1-ylmethyl.
 15. A compoundaccording to claim 1, wherein R² is substituted phenyl or substitutedpyridinyl, wherein substituted phenyl and substituted pyridinyl aresubstituted with one to three substituents independently selected fromthe group consisting of alkoxy and haloalkoxy.
 16. A compound accordingto claim 1, wherein R² is substituted phenyl or substituted pyridinyl,wherein substituted phenyl and substituted pyridinyl are substitutedwith one substituent selected from the group consisting oftrifluoromethyl, 2,2,2-trifluoro-1-hydroxyethyl, isopropoxy and1,1,1-trifluoropropan-2-yloxy.
 17. A compound according to claim 1,wherein R² is substituted phenyl, wherein substituted phenyl issubstituted with one to three substituents independently selected fromthe group consisting of haloalkyl, hydroxyhaloalkyl, alkoxy andhaloalkoxy.
 18. A compound according to claim 1, wherein R² issubstituted phenyl, wherein substituted phenyl is substituted with onesubstituent selected from the group consisting of haloalkyl,hydroxyhaloalkyl, alkoxy and haloalkoxy.
 19. A compound according toclaim 1, wherein R² is substituted phenyl, wherein substituted phenyl issubstituted with one substituent selected from the group consisting oftrifluoromethyl, 2,2,2-trifluoro-1-hydroxyethyl, isopropoxy and1,1,1-trifluoropropan-2-yloxy.
 20. A compound according to claim 1,wherein R² is substituted phenyl, wherein substituted phenyl issubstituted with one substituent selected from the group consisting ofisopropoxy and 1,1,1-trifluoropropan-2-yloxy.
 21. A compound accordingto claim 1, wherein R² is 4-(isopropoxy)phenyl or4-(1,1,1-trifluoropropan-2-yloxy)phenyl.
 22. A compound according toclaim 1, wherein R² is substituted phenyl, wherein substituted phenyl issubstituted with one haloalkyl.
 23. A compound according to claim 1,wherein R² is 4-(trifluoromethyl)phenyl.
 24. A compound according toclaim 1, wherein R² is substituted phenyl, wherein substituted phenyl issubstituted with one hydroxyhaloalkyl.
 25. A compound according to claim1, 16 to 19 or 24, wherein R² is4-(2,2,2-trifluoro-1-hydroxyethyl)phenyl.
 26. A compound according toclaim 1, wherein R² is substituted phenyl, wherein substituted phenyl issubstituted with one alkoxy.
 27. A compound according to claim 1,wherein R² is 4-(isopropoxy)phenyl.
 28. A compound according to claim 1,wherein R² is substituted phenyl, wherein substituted phenyl issubstituted with one haloalkoxy.
 29. A compound according to claim 1,wherein R² is 4-(1,1,1-trifluoropropan-2-yloxy)phenyl.
 30. A compoundaccording to claim 1, wherein R² is substituted pyridinyl, whereinsubstituted pyridinyl is substituted with one to three substituentsindependently selected from the group consisting of haloalkyl,hydroxyhaloalkyl, alkoxy and haloalkoxy.
 31. A compound according toclaim 1, wherein R² is substituted pyridinyl, wherein substitutedpyridinyl is substituted with one substituent selected from alkoxy andhaloalkoxy.
 32. A compound according to claim 1, wherein R² issubstituted pyridinyl, wherein substituted pyridinyl is substituted withone substituent selected from isopropoxy and1,1,1-trifluoropropan-2-yloxy.
 33. A compound according to claim 1,wherein R² is 6-isopropoxypyridin-3-yl.
 34. A compound according toclaim 1, wherein R² is 6-(1,1,1-trifluoropropan-2-yloxy)pyridin-3-yl.35. A compound according to claim 1 of formula (Ia)


36. A compound according to claim 1 of formula (Ib)


37. A compound according to claim 1, selected from the group consistingof:(5α,8α)-8-hydroxy-8-((2-oxopyrrolidin-1-yl)methyl)-2-(4-(trifluoromethyl)phenyl)-2-azaspiro[4.5]decan-1-one;(5α,8α)-8-Hydroxy-8-(2-oxo-piperidin-1-ylmethyl)-2-(4-trifluoromethyl-phenyl)-2-aza-spiro[4.5]decan-1-one;(5α,8α)-8-hydroxy-2-(4-isopropoxyphenyl)-8-((2-oxopyrrolidin-1-yl)methyl)-2-azaspiro[4.5]decan-1-one;(5α,8α)-8-hydroxy-2-(4-isopropoxyphenyl)-8-((2-oxopiperidin-1-yl)methyl)-2-azaspiro[4.5]decan-1-one;(5α,8α)-8-(2,2-Difluoro-ethoxymethyl)-8-hydroxy-2-(4-isopropoxy-phenyl)-2-aza-spiro[4.5]decan-1-one;(5α,8α)-8-Hydroxy-2-(6-isopropoxy-pyridin-3-yl)-8-(2-oxo-pyrrolidin-1-ylmethyl)-2-aza-spiro[4.5]decan-1-one;(5α,8α)-8-hydroxy-2-(6-isopropoxypyridin-3-yl)-8-((2,2,2-trifluoroethoxy)methyl)-2-azaspiro[4.5]decan-1-one;(5α,8α)-8-Hydroxy-8-(2-oxo-pyrrolidin-1-ylmethyl)-2-[4-((R)-2,2,2-trifluoro-1-hydroxy-ethyl)-phenyl]-2-aza-spiro[4.5]decan-1-one;(5α,8α)-8-hydroxy-8-((2-oxopyrrolidin-1-yl)methyl)-2-(4-((R)-1,1,1-trifluoropropan-2-yloxy)phenyl)-2-azaspiro[4.5]decan-1-one;(5α,8α)-8-hydroxy-8-((2-oxopyrrolidin-1-yl)methyl)-2-(6-((S)-1,1,1-trifluoropropan-2-yloxy)pyridin-3-yl)-2-azaspiro[4.5]decan-1-one;(5α,8α)-8-((2-fluoroethoxy)methyl)-8-hydroxy-2-(6-((S)-1,1,1-trifluoropropan-2-yloxy)pyridin-3-yl)-2-azaspiro[4.5]decan-1-one;(5α,8α)-8-((2-fluoroethoxy)methyl)-8-hydroxy-2-(4-isopropoxyphenyl)-2-azaspiro[4.5]decan-1-one;and pharmaceutically acceptable salts thereof.
 38. A compound accordingto claim 1, selected from the group consisting of:(5α,8α)-8-hydroxy-2-(4-isopropoxyphenyl)-8-((2-oxopyrrolidin-1-yl)methyl)-2-azaspiro[4.5]decan-1-one;(5α,8α)-8-(2,2-Difluoro-ethoxymethyl)-8-hydroxy-2-(4-isopropoxy-phenyl)-2-aza-spiro[4.5]decan-1-one;(5α,8α)-8-((2-fluoroethoxy)methyl)-8-hydroxy-2-(6-((S)-1,1,1-trifluoropropan-2-yloxy)pyridin-3-yl)-2-azaspiro[4.5]decan-1-one;and pharmaceutically acceptable salts thereof.
 39. A pharmaceuticalcomposition comprising a compound according to claim 1 and atherapeutically inert carrier.